Copper II complexes of 6-methoxy-1-phenazinol 5,10-dioxide generally are prepared by combining a solution of 6-methoxy-1-phenazinol 5,10-dioxide (myxin) with a solution of a copper II salt. The precursor, 6-methoxy-1-phenazinol 5,10-dioxide, is readily prepared by selective alkylation of iodinin (1,6-phenazinediol 5,10-dioxide) as, for example, by treating the monosodium salt of iodinin with an alkylating agent such as di-methyl sulfate in an inert organic solvent. A solution of 6-methoxy-1-phenazinol 5,10-dioxide when combined with a solution of a cupric salt, e.g., cupric acetate, forms a copper complex containing one mole of copper for every two moles of 6-methoxy-1-phenazinol 5,10-dioxide. Other suitable cupric salts include those of weak acids having pKa's of about 4.2 or higher such as the lower alkanoic acids, e.g., acetic acid or propionic acid and benzoic acid. The salts of mineral acids, such as cupric sulfate, can also be used but they must be used in buffered solvent systems to avoid highly acidic conditions.
Chemically, copper can exist in ionized form in two combining states - the reduced state, i.e., cuprous or copper I, having a valence of .sup.+1 and the oxidized state, i.e., cupric or copper II, having a valence of .sup.+2.
This reaction can be carried out at room temperature or temperatures above room temperature can be used to facilitate solution of the reactants and reduce the amount of solvent needed. Since it is desirable to precipitate the final product from the reaction medium, it is preferred to utilize a solvent or solvent mixture in which both the 6-methoxy-1-phenazinol 5,10-dioxide and the cupric salt are more soluble than the complex formed by their reaction. Exemplary organic solvents which can be conveniently employed include acetonitrile, dimethyl formamide, methanol, ether, chloroform, etc.
The copper II complex of 6-methoxy-1-phenazinol 5,10-dioxide has a high degree and wide spectrum of anti-microbial activity in both in vitro studies and in vivo topical infections. In particular, the copper complex has demonstrated a high level of activity against a wide variety of both gram positive and gram negative bacteria, fungi, protozoa and helminths. This wide spectrum of anti-microbial activity has manifested itself by the efficacy of the copper complex as a chemotherapeutic agent in combatting topical infections.
The copper complex of 6-methoxy-1-phenazinol 5,10-dioxide is physically unsuitable for use alone, i.e., without suitable excipients, in the treatment of topical microbial infections. However, the copper complex, when used in certain topical formulations, i.e., creams and suspensions, while efficacious, is unstable on storage.
There is thus a need for a method of stabilizing such compositions.